Composition and method for medical imaging of body cavities

ABSTRACT

The invention pertains to a foamed aqueous image enhancing composition containing cellulose and/or cellulose derivative(s), said composition having a pH between 5.5 and 7, wherein the viscosity of the composition is less than 1800 mPa.sec, and wherein a gas is maintained in the composition for at least 1 minute after preparation. The combination of low viscosity and foam stability makes the composition particularly suitable in patency tests and fallopian tube sterilization checks.

CROSS-REFERENCE TO RELATED APPLICATION(S)

This application is a continuation of U.S. patent application Ser. No.13/502,232, filed May 25, 2012 as the National Phase of InternationalPatent Application No. PCT/NL2010/050679, filed Oct. 15, 2010 whichclaims priority to Netherland Application No. 2003660, filed Oct. 16,2009. The contents of these applications are herein incorporated byreference in their entirety.

FIELD OF THE INVENTION

This invention relates to compositions and methods for medical imagingof the human or animal body, in particular to medical imaging with highcontrast. More in particular, it pertains to image enhancing agentssuitable in a patency test or in verifying fallopian tube sterilization.

BACKGROUND OF THE INVENTION

Medical diagnostic imaging is widely used for the examination of bodycavities. A prerequisite for the imaging of body cavities is theinstillation of a fluid in order to obtain a fluid-filled cavity. Inthese fluid-filled cavities, the fluid has two functions: (1) to open upthe cavity from its “collapsed” state (distension) and (2) to enhancethe contrast of the image of the body cavity. Conventionally, water orwatery fluids are used for distension and contrast imaging. Inintervention cardiology or radiology, kidneys, liver, intestines, thisis sometimes combined with the generation of bubbles, to furtherincrease contrast in the veins. Examples of so-called microbubbles aregiven by U.S. Pat. No. 4,681,119.

Disadvantageously, the gas contained in these watery fluids disappearsalmost instantaneously, and would thus require continuous replenishmentduring imaging. However, this is often not very convenient for thepatient.

On the other hand, EP 1,793,860 provides a solution to overcome theinconveniences and discomfort caused by leakage of aqueous solutionswhile imaging. Thereto, it discloses a gel composition having aviscosity of between 2000 and 4000 mPa.sec, containing cellulose orcellulose derivative. The composition may be used for the imaging of anybody cavity. The commercially available ExEm® falls within the scope ofEP 1,793,860. The gel is stable and does not contain any particles ormicrobubbles. In fact, these are considered to give rise to artefacts.Where excellent results are reported for the ExEm® e.g. when imaging thecontent of the uterine cavity, the composition appears not particularlysuited when performing a patency test, i.e. to examine the fallopiantubes for blockage, either desired or undesired. It requiresconsiderable pressure (causing pain to the patient) to insert the gelinto the tubes, and even then it appears not feasible. In that respect,it is noted that it is of the essence that any difficulties experiencedby inserting distenting media into the tubes should not be mistaken forreal (permanent) blockage of the fallopian tubes.

Previously, an ultrasound contrast agent ECHOVIST was marketed bySchering AG, which agent consisted of a suspension of micron-sized airbubbles, formed upon reconstitution of specially formulated galactosegranules with an aqueous galactose solution. Amongst other drawbacks,its ingredients and tedious preparation made it a costly tool tovisualize the fallopian tubes. It appears no longer available on themarket.

Outside the field of the invention, US 2003/0206862 describes a contrastmedium for intraveous administration, wherein small gas bubbles areintroduced into the bloodstream. The ultrasound contast medium containssolid polyoxyethylene-660-12-hydroxystearate particles. It goes withoutsaying that the intravenous applications taught in US 2003/0206862 putless constraints to the use of solid particles, while the skilled personin the field of sterilization and fertility investigations is searchingfor particle-free, embryotoxic-free solutions. Adhesion is to beprevented at all cost.

There is thus a need in the art for a simplified, cost-effective agentfor imaging of fallopian tubes which is easy-to-handle, enables highquality images without jeopardising the health of the patient andwithout loss of echogenicity during imaging.

SUMMARY OF THE INVENTION

In view of the above objectives, it has been found that filling of thefallopian tubes and associated visualization while imaging can beimproved when foaming an image enhancing composition such as thataccording to EP1793660 prior to imaging. Where the air bubbles improvedvisualisation, the decreased viscosity enables the medical examiner toinsert the composition without excessive force, even through the smallfallopian tubes. The composition is sufficiently viscous to provide astable distribution of gas bubbles during examination, while at the sametime its viscosity is low enough to assure that it could be insertedinto the fallopian tubes, without excessive force and associated painfor the patient. Hence, the composition does not interfere with thediagnosis whether the fallopian tubes are open or closed. After all,when diagnosing “blockage”, the medical practitioner must be certainthat the composition could have accessed the tubes if it were not forthe blockage. At the conditions given here below, it was found that thecomposition according to the invention can hold the air pockets for atime sufficiently long to perform imaging without loss of echogenicity,and without the need for replenishment.

The composition is free from particulate material and particularlysuited for evaluation of tubal patency in infertility investigations,and as a control on fallopian tube sterilization. Also, fertilityenhancing effects have been ascribed to the composition according toEP1793660, which—without wishing to be bound to any theory—areassociated with the lubricating effect of the composition.

The foamed image enhancing composition has also been found convenientwhen imaging body cavities other than the fallopian tubes, scanning forabnormalities, particularly when determining the shape and/or size ofbody cavities. The foamed composition provides great contrast and easyaccess to all parts of the cavities, thus yielding a sharp contrastbetween the cavity and its walls. The uterus is specifically preferred.

BRIEF DESCRIPTION OF THE FIGURES

FIGS. 1 and 2 show images showing fallopian tubes completely filled withthe foamed composition according to the invention. For enhanced contrastin the application, the negatives corresponding to the original imagesare presented.

DETAILED DESCRIPTION

In one aspect, the present invention relates to a foamed aqueous imageenhancing composition containing cellulose and/or cellulosederivative(s), for improved imaging of a body cavity, particularly thefallopian tubes, wherein the viscosity of the composition is less than1800 mPa.sec, as determined by standard viscosity determination methods,measured at room temperature and under atmospheric pressure. Unlessmentioned otherwise, the viscosity numbers in the context of theinvention are the dynamic viscosities determined using a Brookfieldrotational viscometer , at room temperature (i.e. 25° C.). With “foamed”it is understood that the gas inserted into the composition ismaintained within the composition for at least 1 minute, more preferablyat least 2 minutes, more preferably at least 5 minutes, most preferablyat least 10 minutes, after preparation. All this time, the gas bubblesintroduced mechanically will be maintained in the composition. Althoughnot considered detrimental to the invention, foam stability over timeperiods extending beyond 20 minutes are not preferred. Over the abovetime periods, the foam is considered stable. To keep it simple andcost-effective, it is preferred that the gas is or comprises ambientair. The composition is non-embroyotoxic.

Cellulose derivatives comprise cellulose ethers preferably selected fromalkyl celluloses, hydroxyalkyl celluloses and hydroxyalkyl alkylcelluloses. Examples of suitable cellulose ethers are methylcellulose(MC), ethylcellulose (EC), hydroxyethyl cellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropyl methylcellulose (HPMC), hydroxypropylethylcellulose (HPEC), ethylhydroxyethylcellulose (EHEC), hydroxyethylmethylcellulose (HEMC), and the like. Hydroxyethylcellulose is mostpreferred.

The pH value of the composition is buffered in the range between about5.5 and about 7.5. Preferably, between about pH 6.0 and about 7.0, morepreferably between about pH 6.3 and about 6.8.

The viscosity of the foamed composition is preferably less than 1500mPa.s, more preferably less than 1000 mPa.s, most preferably less than800 mPa.s, particularly less than 500 mPa.s. The actual viscosity may bereadily set by the medical examiner when preparing the foam, dependingon the application: Lower viscosities are particularly preferred whenexamining the fallopian tubes after fallopian tube sterilizationsurgery. At lower viscosities, the risk of pressure build-up, pain andpotential damage to the tubes is avoided. The lower viscosities mayhowever necessitate catheters. It is preferred that the viscosity of thecomposition is more than 4, 5, 10, 15, 20, 30, 40, 50, 80, 100 mPas.This way leakage of image enhancing composition is minimized, and foamstability is guaranteed. The composition may be used in connection withcatheters known in the art. Excellent results are obtained with thesealing stopper and assembly disclosed in WO2007/030002, hereinincorporated by reference.

The skilled person will understand that adjuvants, such as disinfectantsor a local anaesthetic, may be present in the composition, for instancelidocaine and chlorohexidine. It may be preferred to use suchanaesthetics when examining after intratubal placement. In otherembodiments the use of local anaesthetics is not preferred or evenavoided. The composition preferably further contains one or morelubricants, preferably glycerine. If lubricants other than glycerine areemployed, these should be non-embryotoxic (i.e. anything which canadversely affect the growth or development of the embryo). In additioncontrast enhancers may be added, such as iodine for X-ray imaging.However, in a preferred embodiment of the invention the solid content ofthe gel consists substantially of a cellulose derivative, such ashydroxyethylcellulose or methylcellulose in a buffer, and glycerine. Thecomposition of the invention consists of substances which are safe foruse in the human or animal body. It should be echo-lucent and thereforenot contain particulate material, such as starch. Suitably, thecomposition is clear and does not contain particles or protein. It isalso considered non-embryotoxic.

The present invention also pertains to a method for preparing such afoamed composition by (i) providing an aqueous (gel) compositioncontaining cellulose and/or cellulose derivative(s), having a viscosityranging between 2000 and 4000 mPa.sec, and a pH between 5.5 and 7, and(ii) inserting air, alone or in combination with aqueous solution, intosaid composition (i.e. foaming), to produce a foamed compositioncontaining air bubbles or pockets and having a viscosity decreased toacceptable levels. The “insertion” can be realized by all means thatresult in foaming, typically mechanically, by pumping. A suitablecomposition to be foamed is given by EP 1.793.860, its contents hereinincorporated by reference. Here below, the highly viscous raw materialis referred to as the gel composition, thus distinguishing from thefoamed composition according to the invention.

The gel composition provided comprises cellulose or a cellulosederivative as described above. The amount of cellulose or cellulosederivative is to achieve a viscosity of between 2000 and 4000 mPa.sec.,preferably between 2000 and 3000 mPa.sec. The composition thus exhibitsgel-like behaviour. The cellulose (derivatives) play an important rolein retaining the air bubbles. It is preferred that the gel compositioncontains between 1 and 5% cellulose (and/or derivatives).

The skilled person will understand that adjuvants, such as disinfectantsor a local anaesthetic, may be added. The composition preferablycontains non-embryotoxic lubricant(s), preferably at least glycerine. Ifglycerine is present, it preferably contributes in amounts between 1 and10% based on the total gel composition. In addition contrast enhancersmay be added, such as iodine for X-ray imaging. However, in a preferredembodiment of the invention the solid content of the gel consistssubstantially of a cellulose derivative, such as hydroxyethylcelluloseor methylcellulose, in a buffer, and glycerine. A suitable gelcomposition is commercially available under the name of ExEm®.

The pH value is as described above, and—in view of the above—thecomposition consists of substances which are safe for use in the humanor animal body. It should be echo-lucent and therefore not containparticulate material, such as starch.

Although there are no limitations regarding the ways to insert airpockets into the gel, this may conveniently be achieved by pumping air,and (demineralised or purified) water or saline salt solution, bothconsidered included in the term “aqueous solution”, into the gelcomposition. Conveniently, this may be performed by the practitioner orassistant in the presence of the patient immediately prior to imaging,preferably by connecting a first syringe, containing a predeterminedamount of the gel composition, with a second syringe, filled with air ora predetermined amount of aqueous solution, and pumping the contents ofthe second syringe and the first syringe back and forth, until asuitable foam is formed. The syringes may be connected using simple(medical) tubing, optionally with a mixing chamber in between.

In one embodiment, foaming is realized by pumping air into the aqueousgel composition, i.e. no water added to the gel composition. This willresult in foamed compositions having a viscosity at the higher end ofthe above range, and is found particularly useful when examining a bodycavity for its shape. The bubbles are found to improve the image. Inthese cases, problems caused by administering the relatively viscouscomposition into the cavity are of less concern.

However, in a preferred embodiment, the gel composition is foamed usingan aqueous solution and air, particularly where imaging concerns apatency test or a fallopian tube sterilization check. The relativeamounts of the gel composition and the aqueous solution are selectedsuch that the end viscosity is within the desired range. The desiredviscosity may conveniently be assessed by the medical practitioner, andhe may adjust the amount of aqueous solution mixed with the gelcomposition according to his or her needs. A syringe containing the(maximum allowable amount of) aqueous solution, said syringe having acalibrated scale, preferably even in combination with an instructionmanual that helps to convert the numbers in terms of viscosities, may beof help. As a guide, the volume ratio aqueous solution: gel compositionis preferably at least 1:99. More preferably, the relative volume ratiobetween the aqueous solution and the gel composition ranges between10:90 and 90:10 (vol %), more preferably between 20:80 and 80:20, evenmore preferably between 30:70 and 70:30, more preferably between 40:60and 60:40. The actual mixing ratio depends on the purpose of theexamination; in case of patency test, significant amounts of water arepreferred; excellent results are obtained at a 50:50 ratio (vol %). Theabove numbers on cellulose and optional glycerine content can readily berecalculated to the foamed and diluted composition.

The present invention also pertains to a kit of parts comprising (i) anaqueous image enhancing composition comprising cellulose or cellulosederivate, said composition having a viscosity ranging between 2000 and4000 mPa.sec, as determined by standard viscosity determination methods,measured at room temperature and under atmospheric pressure; and (ii) anaqueous solution (purified or demineralised water or a saline solution).Both (i) and (ii) are preferably provided in a sealed and sterilizedstate, preferably in a syringe. A suitable composition (i) iscommercially available by the name of ExEm®. Optionally the kit alsocomprises means for connecting both syringes to one another, e.g. apiece of medical tubing. The entire kit can be disposed of afterpreparing the foam and the treatment/examination has taken place. Forsake of completeness, solution (ii) has a viscosity corresponding tothat of water, and contains no viscosity increasing agents.

Conveniently, the syringes may be filled with the gel composition (i)and the aqueous composition (ii) in pre-determined amounts, to achieve amixing ratio as described above. In one embodiment, the syringe (ii)contains the aqueous solution in an amount that corresponds with themaximum allowable amount to achieve a low-viscous stable foam. Forinstance, syringe (ii) contains an amount of aqueous solution withrespect to syringe (i) containing the gel composition that correspondsto a volume ratio in the range of 80:20 to 99:1 (vol %), preferablyaround 90:10 (vol %).

In yet another aspect, the invention pertains to a method for imagingthe (shape and/or size of) and/or diagnosing for abnormalities of a bodycavity in a patient, said method comprising administering theabove-described foamed image enhancing composition to the patient, andscanning the patient using imaging.

The image enhancing composition of the invention may be used for alltypes of medical imaging, including X ray imaging, echography, magneticresonance imaging, CT scanning and ultrasound imaging. Preferably, theyare used for ultrasound imaging. More preferably, it is used for3-dimensional ultrasound imaging. In one embodiment, the compositions ofthe invention are used in 3-dimensional sonohysterography. As usedherein, “image enhancement” refers to increasing the contrast of animage. The contrast enhancement may be either negative (black) orpositive (white).

Typically, enhancement also involves distension of the body cavity ofwhich an image is made. The compositions of the invention may be usedfor the imaging of any body cavity, including each part of thegastro-intestinal tract, such as the stomach, the colon. the duodenum;the bladder, the vagina. In a preferred embodiment, the body cavity isthe uterine cavity. The foamed composition is found particularly usefulin evaluating the size and shape of the cavity.

A medium comprising a composition of the invention may be administeredor introduced in a body cavity by methods known in the art and dependingon the body cavity which is to be examined. For instance, forexamination of the uterus, the composition is typically administered viaan instillation device, such as a catheter. The method comprisesintroducing the foamed composition in small aliquots in the body cavity.The skilled person will understand that the amount which has to beadministered or introduced will be dependent on the size of the bodycavity which has to be imaged. Typically, about 1-10 ml will be enoughfor most cavities. Constant infusion is not necessary.

In a preferred embodiment, the invention pertains to the use of thefoamed image enhancing composition in a patency test, i.e. to determinewhether the fallopian tubes are open or closed. The composition of theinvention can be applied in a control on anti-conception methods knownin the art, particularly in combination with Adiana®, Essure® andOvabLoc® intratubal devices. Typically such a test is performed within 3to 6 months after fallopian tube sterilization surgery or intratubalplacement.

In yet another aspect, the invention provides for high contrast imageswhich are obtainable by using the compositions of the invention. Alsoencompassed in the invention, are high contrast 3-dimensional images. Inparticular, high contrast 3-dimensional images of the fallopian tubes.In a preferred embodiment, the invention is used for so-called virtualhysteroscopy. Three dimensional imaging requires a very stable and quietfilling of the cavity of interest, with a minimum amount of artefacts.

EXAMPLE

This example demonstrates how the compositions and method of theinvention may effectively and safely be used for sonohysterography.

A syringe containing 10 ml of a sterile, clear viscous gel containinghydroxyethylcellulose, glycerine, buffered with acetic acid [Exem®(GIS-kit B.V.)] was connected to another syringe containing 10 mldemineralised water, using small plastic tubing. The water was nowpumped into the other syringe, and back. This was repeated for 5 times,until a foam was produced. The dynamic viscosity as measured usingBrookfield rotational viscometry at 25° C. was about 250 mPas.

The foamed composition was now used for sonohysterography and introducedinto the fallopian tubes using conventional ways. There was no excessforce and the patients experienced no pain. The foam was stable duringimaging. A clear image of the fallopian tubes could thus be provided,see FIGS. 1 and 2.

1. A foamed aqueous image enhancing composition containing celluloseand/or cellulose derivative(s), said composition having a pH between 5.5and 7, wherein the viscosity of the composition is less than 1800mPa.sec as determined by standard viscosity determination methods,measured at room temperature and under atmospheric pressure, and whereina gas is maintained in the composition for at least 1 minute afterpreparation.
 2. The foamed composition according to claim 1, wherein theviscosity is at least 15 mPas.
 3. The foamed composition according toclaim 1, wherein the viscosity is less than 1000 mPa.s.
 4. A kit ofparts, comprising: (i) An aqueous image enhancing composition comprisingcellulose and/or cellulose derivate(s), said composition having aviscosity ranging between 2000 and 4000 mPa.sec, as determined bystandard viscosity determination methods, measured at room temperatureand under atmospheric pressure; and (ii) an aqueous solution.
 5. The kitof parts according to claim 4, wherein the composition (i) and solution(ii) are provided in pre-determined amounts comprised in syringes. 6.The kit of parts according to claim 5, wherein the volume ratio ofsolution (ii) with respect to composition (i) is in the range of 80:20to 99:1.
 7. The kit of parts according to claim 4, wherein said aqueoussolution (ii) is demineralised water or saline solution.
 8. Use of acomposition according to 1 in a medical imaging procedure of a bodycavity.
 9. Use according to claim 8, wherein said body cavity is thefallopian tubes.
 10. Use of a kit of parts according to claim 4 in amedical imaging procedure of a body cavity.
 11. Use according to claim10, wherein said body cavity is the fallopian tubes.
 12. A method forpreparing a foamed aqueous image enhancing composition, by (i) providingan aqueous image enhancing composition containing cellulose and/orcellulose derivative(s), having a pH in the range of 5.5 and 7, andviscosity ranging between 2000 and 4000 mPa.sec as determined bystandard viscosity determination methods, measured at room temperatureand under atmospheric pressure, and (ii) foaming said composition, toproduce a foamed composition having a viscosity less than 1800 mPa.s atroom temperature.
 13. The method according to claim 12, wherein foaminginvolves a combination of air and aqueous solution.
 14. Use of thecomposition according to claim 1 in a patency test or in a check onfallopian tube sterilization surgery.
 15. Use according to claim 14,wherein said surgery involves Adiana®, Essure® or OvabLoc® intratubaldevices.
 16. Use of the kit of parts according to claim 4 in a patencytest or in a check on fallopian tube sterilization surgery.
 17. Useaccording to claim 16, wherein said surgery involves Adiana®, Essure® orOvabLoc® intratubal devices.
 18. A method for enhancing contrast of animage of a body cavity, which method comprises introducing once 1-10 mlof an image enhancing composition according to claim 1 into the bodycavity.
 19. The method according to claim 18, wherein said body cavityis uterus or the fallopian tubes.
 20. The method according to claim 19,wherein said body cavity is the fallopian tubes.
 21. A method fordiagnosing for abnormalities of a body cavity in a patient, said methodcomprising (a) administering the foamed composition according to claim 1to the patient, and (b) scanning the patient using imaging.